Table Of ContentCYCLOSPORIN
MODE OF ACTION AND CLINICAL APPLICATIONS
CYCLOSPORIN
Mode of Action and Clinical Applications
Edited by
Angus W. Thomson
BSc(Hons), MSc, PhD, DSc, MRCPath, Fmiol
Reader in Immunology
Department of Pathology
University of Aberdeen
Foresterhill
Aberdeen
Scotland
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for all other countries: Kluwer Academic Publishers Group. Distribution
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British Library Cataloguing in Publication Data
Cy closporin.
1. Man. Organs and tissues. Transplantation. Drug therapy. Cyclosporin A
I. Thomson Angus W.
615'.7
ISBN-l3: 978-94-010-6874-1 e-ISBN-l3: 978-94-009-0859-8
001: 10.1007/978-94-009-0859-8
Copyright
(j'? 1989 by Kluwer Academic Publishers
Softcover reprint of the hardcover 1s t edition 1989
All rights reserved. No pari of this publication may be reproduced. stored in a retrieval system. or
transmitted in any form or by any means. electronic. mechanical. photocopying. recording or otherwise.
without prior permission from the publishers. Kluwer Academic Publishers BV. PO Box 17. 3300 AA
Dordrecht. The Netherlands.
Published in the United Kingdom by Kluwer Academic Publishers. PO Box 55. Lancaster. UK.
Kluwer Academic publishers BV incorporates the publishing programmes of D. Reidel. Martinus
Nijhoff. Dr W. Junk and MTP Press.
Typeset by Lasertext. Stretford. Manchester
Contents
List of contributors vii
Foreword
Sir Roy Y. Caine ix
Preface x
1 Inhibitory effects of C'yduspoh"'r1 A or- Iy.thphocyte activation
John E. Kay 1
2 Effect of cyclosporin A on the immune response: pivotal role
of the interleukin-2/interleukin-2 receptor autocrine pathway
Allan D. Hess 24
3 Influence of cyclosporin A on humoral immunity and on B
lymphocyte activation
Iris Moffa and Paolo Truffa-Bachi 34
4 The influence of cyclosporin A on T cell activation, cytokine
gene expression and cell-mediated immunity
Angus W. Thomson and Janet 1. Duncan 50
5 Cyclosporin A and tolerance induction in experimental
animals
Susan M. L. Lim and David J. G. White 82
6 Prevention of graft rejection by cyclosporin A in man
Michael C. Jones and Graeme R. D. CaHo 112
7 Cyclosporin A and bone marrow transplantation
Kerry Atkinson 145
8 Cyclosporin A and intraocular inflammatory disease
John V. Forrester, Janet Liversidge and Hamish M. Towler 159
9 Cyclosporin A in insulin-dependent diabetes
Jean-Fran(:ois Bach 181
10 Cyclosporin A and skin disease
Ann V. Powles, Barbara S. Baker and Lionel Fry 191
v
CYCLOSPORIN
11 Cyclosporin A (Sandimmun ®) in autoimmune disorders
Beat von Graffenried, David Friend, Nicholas Shand,
Wi/fried Schiess and PenHi Timonen 213
12 Pharmacokinetics of cyclosporin A
Joachim Grevel and Barry D. Kahan 252
13 Cyclosporin A metabolism and drug interactions
M. Danny Burke, Fiona MacIntyre, D. Cameron
and Paul H. Whiting 267
14 Pathological effects of cyclosporin A in experimental models
Paul H. Whiting and Angus W. Thomson 303
15 Pathological effects of cyclosporin A in clinical practice
Sathia Thiru 324
Index 365
vi
List of Contributors
Kerry Atkinson John V. Forrester
Department of Haematology Department of Ophthalmology
St Vincent's Hospital University of Aberdeen
Sydney Foresterhill
New South Wales, 2010 Aberdeen AB9 2ZD
Australia
David Friend
Jean-Fram;ois Bach Clinical Research
Inserm U 25 CNRS U 122 Sandoz Ltd
Hopital Necker CH-4002
161 Rue de Sevres 75015 Basle
Paris Switzerland
France
Lionel Fry
Barbara S. Baker
Department of Dermatology and
Department of Dermatology and
Immunology
Immunology
St Mary's Hospital
St Mary's Hospital
London W2 1NY
London W2 INY
M. Danny Burke Joachim Grevel
Department of Pharmacology Division of Immunology and Organ
University of Aberdeen Transplantation
Marischal College The University of Texas Medical School
Aberdeen AB9 lAS 6431 Fannin MSB 6.252
Houston
Texas 77030
D. Cameron
USA
Department of Pharmacology
University of Aberdeen
Marischal College Allan D. Hess
Aberdeen AB9 lAS The Bone Marrow Transplant Unit
Oncology Centre
Graeme R. D. Catto The Johns Hopkins University
Department of Medicine and Therapeutics 600 N. Wolfe St
University of Aberdeen Baltimore
Foresterhill Maryland 21205
Aberdeen AB9 2ZD USA
Janet I. Duncan Michael C. Jones
Immunopathology Laboratory Department of Medicine and Therapeutics
Department of Pathology University of Aberdeen
University of Aberdeen Foresterhill
Aberdeen AB9 2ZD Aberdeen AB9 2ZD
vii
CYCLOSPORIN
Barry D. Kahan Sathia Thiru
Department of Immunology and Organ Department of Pathology
Transplantation Cambridge University
The University of Texas Medical School Addenbrooke's Hospital
643 Fannin, MSB 6.151 Cambridge CBl lQQ
Houston
Texas 77030
Angus W. Thomson
USA
Immunopathology Laboratory
John E. Kay Department of Pathology
School of Biological Sciences and Centre for University of Aberdeen
Medical Research Foresterhill
University of Sussex Aberdeen AB9 lZD
Brighton BNI 9QG
Susan M. l. Lim Pentti Timonen
Department of Surgery Clinical Research
Level 9 Sandoz Ltd
Addenbrooke's Hospital CH-4001
Cambridge CBl lQQ Basle
SwitzerlaRd
Janet Liversidge
Department of Ophthalmology
University of Aberdeen Hamish M. Towler
Foresterhill Department of Ophthalmology
Aberdeen AB9 lZD University of Aberdeen
Fiona Macintyre Foresterhill
Department of Pharmacology Aberdeen AB9 lZD
University of Aberdeen
Marischal College Paolo Truffa-Bachi
Aberdeen AB9 lAS Unite d'Immunophysiologie Moleculaire
Iris Motta Institut Pasteur
Unite d'Immunophysiologie Moleculaire 75724
lnstitut Pasteur Paris Cedex 15
75724 France
Paris Cedex 15
France Beat von Graffenried
Anne V. Powles Clinical Research
Department of Dermatology and Sandoz Ltd
Immunology CH-4001
St Mary's Hospital Basle
London Wl INY Switzerland
Wilfried Schiess
Clinical Research David J. G. White
Sandoz Ltd Department of Surgery
CH-4001 Level 9
Basle Addenbrooke's Hospital
Switzerland Cambridge CBl lQQ
Nicholas Shand
Clinical Research Paul H. Whiting
Sandoz Ltd Department of Clinical Biochemistry
CH-4001 University of Aberdeen
Basle Foresterhill
Switzerland Aberdeen AB9 lZD
viii
Foreword
Cyclosporin has had a remarkable effect on clinical organ transplantation.
Prior to its introduction, considerable advances had been made in the grafting
of vital organs, particularly the kidney, heart and liver. In many developed
countries, however, transplantation was not considered wo-rthwhile in terms
of gain for the investment of resources. The improved results of kidney grafts
following the use of cyclosporin has changed this attitude. For all types of
organ transplantation, cyclosporin has resulted in an improvement of functional
graft survival and has allowed a reduction in steroid dose and, in some
cases, no steroids at all. It has permitted the first successful experimental
transplantation of the heart and lungs in primate species by Reitz and
colleagues and their results were applied directly to the clinic. It was largely
due to the introduction of cyclosporin that the Washington Consensus
Meeting on Liver Transplantation came to a favourable recommendation and
the result has been the proliferation of units performing liver transplantation,
approximately fifty in North America and another fifty in Europe, where
previously there had been a handful.
Having been involved in cyclosporin for organ grafting from the beginning,
I have been able to witness these developments which have far exceeded my
expectations once the nephrotoxicity of cyclosporin was demonstrated in
man. It is fitting that Dr. Thomson has put together this important volume
of the state of the art of cyclosporin, since he has been one of the leaders in
the investigation of its mode of action and side effects. He has brought
together a strong team of authors and I am sure that their combined wisdom
will be of great use to scientists and clinicians working in transplantation and
on autoimmunity. The bibliography will be especially valuable.
It is my pleasure to be associated with this book and to write the Foreword.
Sir Roy CaIne FRS
University of Cambridge
May, 1989.
ix
Preface
The advent of a novel immunosuppressive agent with the distindive anti-T
cell properties of cyclosporin came by fortune rather than by design. We still
do not comprehend how it exercises its seledivity for helper T cells or how,
in precise molecular terms, it suppresses their adivation. Since the first
descriptions in 1976 of its immunological properties by J. F. Borel and his
colleagues in BaseL and since its introdudion into clinical use by R. Y. Caine
in Cambridge, cyclosporin has been the subject of several thousands
of scientific papers. Three major international congresses on cyclosporin
(Cambridge, Houston and Washington) have been held, whilst in the clinic,
the drug has had a major impad on the nature of, and progress in, clinical
organ transplantation.
Cyclosporin has proved a powerful investigative tool for immunologists
in the evaluation and dissedion of T cell fundi on. Its potential for the
treatment of certain autoimmune diseases in which T cells are believed to
playa pathogenetic role is presently the subjed of extensive investigation.
In this book, the mode of adion, clinical applications, pharmacology and
pathology of cyclosporin are reviewed by expert contributors in Europe,
North America and Australia. I am grateful to them all for their roles in this
venture.
A. W. Thomson
University of Aberdeen
May, 1989.
x
1
Inhibitory effects of cyclosporin A on
lymphocyte activation
John E. Kay
Il\.1MUNOSUPPRESSION BY CYCLOSPORIN A
Cyclosporin A (CsA) was first identified in the early 1970s by Dr J. F. Borel
and colleagues of Sandoz Ltd as a compound in the culture broths of the
fungi Tolypocladium inf/atum and Cylindrocarpon lucidum that showed strong
in vivo immunosuppressive activity in mice, but was otherwise well tolerated.
Their influential publication on the properties of CsA in 19761 led to successful
clinical trials, and the drug is now in routine use in organ transplantation. It
also shows promise in the prevention or treatment of some conditions with
an autoimmune basis (discussed in subsequent chapters of this volume). It
was very quickly apparent that CsA differed in its mechanism of action from
pre-existing immunosuppressive drugs, in that at therapeutic concentrations
it showed no general inhibition of cell proliferation and was not cytotoxic to
lymphocytes.
STRUCTURE AND ANALOGUES
CsA is a strongly hydrophobic cyclic endecapeptide, with a relative molecular
mass of 1202. Its structure, first determined in 1976, it shown in Figure 1.1.
It contains a 9-carbon amino acid at position I that had not previously been
discovered, appears to be unique to cyclosporins and is essential for biological
activity. Seven of the amino acids are N-methylated, and one (at position 8)
is in the 0 configuration. The total synthesis of this molecule has been
achieved, and the properties of a large number of natural and synthetic
analogues are reviewed in references 2 and 3. None of the analogues so far
studied has proved more potently immunosuppressive than CsA. though one
natural analogue in which the C(-aminoisobutyric acid residue at position 2 is
replaced by a norvaline appears to couple similar potency with fewer side
effects4•
